The outcome of adults with acute lymphoblastic leukemia (ALL) remains poor. While 90% of adult patients will achieve an initial remission with chemotherapy, the majority will relapse and only 30-40% will achieve long-term disease free survival. Evidence suggests that similar to normal hematopoietic stem/progenitor cells, leukemic cells receive key growth and survival signals from the bone marrow microenvironment. Moreover, direct physical interaction of leukemic cells with stromal cells in the bone marrow may limit their sensitivity to chemotherapy. Thus, targeting leukemia-stromal interactions is an emerging and promising strategy to sensitize leukemic cells to cytotoxic chemotherapy. Preclinical studies performed by our group suggest that treatment with granulocyte-stimulating factor (G- CSF) provides a potent and well-tolerated method to disrupt the leukemia niche in the bone marrow. Indeed, treatment with G-CSF prior to initiating chemotherapy augments clearance of ALL cells in mice. We initiated a pilot clinical trial of upfront G-CSF treatment prior to salvage chemotherapy in patients with relapsed ALL. Preliminary data show that G-CSF induces mobilization of ALL cells into the blood, while inducing apoptosis of ALL cells resident in the bone marrow. There is strong evidence that CXCL12 provides a key survival signal for normal and malignant lymphocytes. Preliminary data show that treatment with POL5551, a novel and potent CXCR4 antagonist, mobilizes ALL cells into the blood in mice and renders them more sensitive to chemotherapy. Since G-CSF results in only partial suppression of CXCL12 in the bone marrow, we hypothesize that treatment with G-CSF and a CXCR4 antagonist will cooperate to disrupt leukemia-stromal cell signals, rendering ALL cells more sensitive to chemotherapy. The following specific aims are proposed.
Aim 1. To optimize strategies to disrupt the leukemic niche in the bone marrow and sensitize human ALL cells to chemotherapy.
Aim 2. To test the feasibility of priming with G-CSF and POL6326 with chemotherapy in adults with relapsed or refractory ALL.
This proposed research is relevant to public health because it seeks to translate fundamental observations on the effects of G-CSF and CXCR signalling in to an early phase clinical trial with an overall goal of improving the clinical outcomes of patients with acute lymphoblastic leukemia.
|Duncavage, Eric J; Jacoby, Meagan A; Chang, Gue Su et al. (2018) Mutation Clearance after Transplantation for Myelodysplastic Syndrome. N Engl J Med 379:1028-1041|
|Khoury, Hanna Jean; Langston, Amelia A; Kota, Vamsi K et al. (2018) Ruxolitinib: a steroid sparing agent in chronic graft-versus-host disease. Bone Marrow Transplant 53:826-831|
|Schroeder, Mark A; Choi, Jaebok; Staser, Karl et al. (2018) The Role of Janus Kinase Signaling in Graft-Versus-Host Disease and Graft Versus Leukemia. Biol Blood Marrow Transplant 24:1125-1134|
|Perry, Justin S A; Russler-Germain, Emilie V; Zhou, You W et al. (2018) CD36 Mediates Cell-Surface Antigens to Promote Thymic Development of the Regulatory T Cell Receptor Repertoire and Allo-tolerance. Immunity 48:923-936.e4|
|Wong, Terrence N; Miller, Christopher A; Jotte, Matthew R M et al. (2018) Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential. Nat Commun 9:455|
|Christopher, Matthew J; Petti, Allegra A; Rettig, Michael P et al. (2018) Immune Escape of Relapsed AML Cells after Allogeneic Transplantation. N Engl J Med 379:2330-2341|
|Trissal, Maria C; Wong, Terrence N; Yao, Juo-Chin et al. (2018) MIR142 Loss-of-Function Mutations Derepress ASH1L to Increase HOXA Gene Expression and Promote Leukemogenesis. Cancer Res 78:3510-3521|
|Jacoby, Meagan A; Duncavage, Eric J; Chang, Gue Su et al. (2018) Subclones dominate at MDS progression following allogeneic hematopoietic cell transplant. JCI Insight 3:|
|Monlish, Darlene A; Bhatt, Sima T; Duncavage, Eric J et al. (2018) Loss of Toll-like receptor 2 results in accelerated leukemogenesis in the NUP98-HOXD13 mouse model of MDS. Blood 131:1032-1035|
|Choi, Jaebok; Cooper, Matthew L; Staser, Karl et al. (2018) Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease. Leukemia 32:2483-2494|
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